Novel Intervention to Influence Muscle Plasticity in Veterans with SCI The long-term goal is to develop a rehabilitation strategy to prevent the deleterious muscular and metabolic complications (diabetes) that follow individuals with complete spinal cord injury (SCI). Up to 300, 000 persons are living with SCI, and more than 10% receive their care within the VA health system. Secondary complications (muscle atrophy, and diabetes) in the decades after SCI cost society between 4 and 7 billion dollars annually. A method to prevent these complications would not only provide substantial savings, but also could profoundly improve the quality of life of veterans with SCI. Recently, we verified that a certain dose of muscle force maintained the calf muscle of the lower leg for over 2 years following SCI. We now aspire to determine if various doses of muscle force preferentially up regulate protein synthesis pathways, down regulate protein degradation pathways, and improve blood metabolic markers during a novel functional exercise. Three specific aims will address these hypotheses by inducing various doses of stress to the lower extremities during stance and neuromuscular electrical stimulation. Aim 1 will compare 3 tiers of muscle force training induced via (0, 10, and 20 Hz stimulation) on muscle physiological properties (fatigue, force, potentiation) over a 12 week training and detraining period. Aim 2 will compare the effects of 3 muscle forces (0, 10 Hz, 20 Hz) on molecular markers of muscle atrophy. Aim 3 will compare the effects of three muscle forces (0,. 10 Hz, and 20 Hz) on insulin sensitivity and inflammatory markers. The combined effect of cardiovascular stress through stance and muscle activation offers a unique strategy to affect metabolic changes. This study is novel because it uses an intervention that is feasible, quantifiable, portable, and dose of muscle force specific. This research is grounded by sound scientific principles, but also has the potential to rapidly translate to the VA health system to influence health quality. In the next several decades, a cure for spinal cord injury is a realistic possibility. Without a method to preserve the integrity of paralyzed lower limbs, the veterans with SCI injured today will be unable to participate in those trials because of a deteriorated musculoskeletal system. Moreover, preservation of muscular systems may increase insulin sensitivity and improve the veterans overall health today. We believe that future clinical trials will need the dose information from this trial to establish efficacy. This intervention has excellent potential for efficacy, but also is likely to be economical and easily integrated into the daily lives of veterans with SCI. PUBLIC HEALTH RELEVANCE: The significance of this project relates to the breadth of impact this intervention may have on the health of those veterans with SCI. There are several novel components to this study. The findings of this study may affect how we prescribe exercise for those with and without SCI. During volitional activity, we know that muscle force triggers greater protein synthesis responses. However, electrically activating muscle is quite different both mechanically and physiologically from volitional activation of muscle. Moreover, the link between muscle atrophy, diabetes, and bone catabolism may have important implications for the veteran with SCI. Our goal is to eliminate the deteriorating by-products of bone and muscle as a result of muscle loss after paralysis in order to decrease secondary complications and improve the quality of life of our veterans with SCI.